G-protein coupled receptors (GPCRs) are integral membrane proteins characterized by the presence of seven hydrophobic transmembrane domains which span the plasma membrane and form a bundle of antiparallel alpha helices. The transmembrane domains account for structural and functional features of the receptor. In most cases, the bundle of helices forms a binding pocket; however, when the binding site must accommodate more bulky molecules, the extracellular N-terminal segment or one or more of the three extracellular loops participate in binding and in subsequent induction of conformational change in intracellular portions of the receptor. The activated receptor, in turn, interacts with an intracellular heterotrimeric G-protein complex which mediates further intracellular signaling activities, generally interaction with guanine nucleotide binding (G) proteins and the production of second messengers such as cyclic AMP (cAMP), phospholipase C, inositol triphosphate or ion channel proteins (Baldwin, J. M. (1994) Curr. Opin. Cell Biol. 6:180-190).
The amino-terminus of the GPCR is extracellular, of variable length and often glycosylated, while the carboxy-terminus is cytoplasmic and generally phosphorylated. Extracellular loops of the GPCR alternate with intracellular loops and link the transmembrane domains. The most conserved domains of GPCRs are the transmembrane domains and the first two cytoplasmic loops. GPCRs range in size from under 400 to over 1000 amino acids (Coughlin, S. R. (1994) Curr. Opin. Cell Biol. 6:191-197).
GPCRs respond to a diverse array of ligands including lipid analogs, amino acids and their derivatives, peptides, cytokines, and specialized stimuli such as light, taste, and odor. GPCRs function in physiological processes including vision (the rhodopsins), smell (the olfactory receptors), neurotransmission (muscarinic acetylcholine, dopamine, and adrenergic receptors), and hormonal response (luteinizing hormone and thyroid-stimulating hormone receptors).
GPCR mutations, both of the loss-of-function and of the activating variety, have been associated with numerous human diseases (Coughlin, supra). For instance, retinitis pigmentosa may arise from either loss-of-function or activating mutations in the rhodopsin gene. Somatic activating mutations in the thyrotropin receptor cause hyperfunctioning thyroid adenomas (Parma, J. et al. (1993) Nature 365:649-651). Parma et al. suggest that certain G-protein-coupled receptors susceptible to constitutive activation may behave as proto-oncogenes.
Neuropeptide Y (NPY), pancreatic polypeptide (PP), and peptide YY (PYY) are structurally related peptides found in higher vertebrates. NPY is produced in the central and peripheral nervous systems. NPY plays a role in the stimulation of food intake, anxiety, facilitation of learning and memory, and regulation of the neuroendocrine and cardiovascular systems. NPY also stimulates vascular smooth muscle contraction, modulates hormone secretion, and has been implicated in the pathophysiology of hypertension, congestive heart failure, affective disorders and appetite regulation (Watson, S. and S. Arkinstall (1994) The G-Protein Linked Receptor Facts Book, Academic Press, San Diego Calif., pp. 194-198). PP is produced in endocrine cells in the pancreas and inhibits pancreatic secretion, gall bladder contraction, and gut motility. PYY is produced in endocrine cells of the pancreas and large intestine. PYY has actions similar to those of PP, and in addition redistributes blood flow in gut vessels. Both PP and PYY are released into the circulation in response to food intake. These structurally related peptides accomplish their varied biological functions through interaction with distinct GPCR subtypes. Several receptor subtypes have been defined by their ability to bind NPY, PYY, PP, and derivatives of these peptides. At least five distinct receptor subtypes have been characterized to date (Weinberg, D. H. et al. (1996) J. Biol. Chem. 271:16435-16438).
Cholecystokinin (CCK) is a bioactive peptide which is present throughout the digestive tract, and is also found in smooth muscle tissues such as bladder and uterus, in secretory glands such as exocrine pancreas, and in the brain. The major physiological actions of CCK are gall bladder contraction, pancreatic enzyme secretion, and regulation of secretion/absorption in the gastrointestinal tract. CCK receptors are GPCRs found in peripheral tissues including pancreas, stomach, intestine and gall bladder, and in limited amounts in the brain. CCK receptors mediate pancreatic acinar secretion and gallbladder contraction (De Weerth, A. et al. (1993) Am. J. Physiol. 265:G1116-G1121). The CCK-A receptor has been implicated in the pathogenesis of schizophrenia, Parkinson's disease, drug addiction and feeding disorders (Watson and Arkinstall, supra, pp. 89-95).
The discovery of a new human G-protein coupled receptor and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention and treatment of endocrine, neurological, and cardiovascular disorders.